Involvement of Recognition and Interaction of Carnitine Transporter in the Decrease of L-Carnitine Concentration Induced by Pivalic Acid and Valproic Acid

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Abstract

Purpose

Prodrugs with pivalic acid and valproic acid decrease L-carnitine concentration in plasma and tissues by urinary excretion of acylcarnitine as pivaloylcarnitine (PC) and valproylcarnitine (VC), respectively. We investigated the role of the Na+/L-carnitine cotransporter in the porcine kidney epithelial cell line, LLC-PK1 for the decrease of L-carnitine concentration.

Methods

The uptake of L-[3H]carnitine, acetyl-L-[3H]carnitine (AC), L-[3H]PC and L-[3H]VC were investigated in LLC-PK1 cells seeded in a 6-well culture plate.

Results

L-Carnitine and AC uptake in LLC-PK1 cells exhibited Na+ dependency. The Km values for L-carnitine and AC uptake were 11.0 and 8.18 μM, respectively. These results indicated expression of Na+/L-carnitine cotransporter in LLC-PK1 cells. PC and VC inhibited Na+/L-carnitine cotransporter in the competitive (Ki = 90.4 μM) and noncompetitive (Ki = 41.6 μM) manners, respectively. PC and VC uptake by Na+/L-carnitine cotransporter were not observed in LLC-PK1 cells.

Conclusions

These data suggested that PC and VC formed in the body could not be reabsorbed in the kidney, resulting in the decrease of L-carnitine concentration. In addition, inhibition of L-carnitine reabsorption by VC with lower Ki value could induce the decrease of L-carnitine concentration. Collectively, the recognition and interaction of Na+/L-carnitine cotransporter are important factors for carnitine homeostasis.

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